Showing papers on "Anthrax vaccines published in 2006"

Microneedle-based intradermal delivery of the anthrax recombinant protective antigen vaccine.

Abstract: The recombinant protective antigen (rPA) of Bacillus anthracis is a promising anthrax vaccine. We compared serum immunoglobulin G levels and toxin-neutralizing antibody titers in rabbits following delivery of various doses of vaccine by microneedle-based intradermal (i.d.) delivery or intramuscular (i.m.) injection using conventional needles. Intradermal delivery required less antigen to induce levels of antibody similar to those produced via i.m. injection during the first 2 weeks following primary and booster inoculation. This dose-sparing effect was less evident at the later stages of the immune response. Rabbits immunized i.d. with 10 μg of rPA displayed 100% protection from aerosol spore challenge, while i.m. injection of the same dose provided slightly lower protection (71%). Groups immunized with lower antigen doses were partially protected (13 to 29%) regardless of the mode of administration. Overall, our results suggest rPA formulated with aluminum adjuvant and administered to the skin by a microneedle-based device is as efficacious as i.m. vaccination.

Prophylaxis and Therapy of Inhalational Anthrax by a Novel Monoclonal Antibody to Protective Antigen That Mimics Vaccine-Induced Immunity

Abstract: The neutralizing antibody response to the protective antigen (PA) component of anthrax toxin elicited by approved anthrax vaccines is an accepted correlate for vaccine-mediated protection against anthrax. We reasoned that a human anti-PA monoclonal antibody (MAb) selected on the basis of superior toxin neutralization activity might provide potent protection against anthrax. The fully human MAb (also referred to as MDX-1303 or Valortim) was chosen from a large panel of anti-PA human MAbs generated using transgenic mice immunized with recombinant PA solely on the basis of in vitro anthrax toxin neutralization. This MAb was effective in prophylactic and postsymptomatic treatment of rabbits exposed to aerosolized anthrax spores, and a single intramuscular injection of 1 mg/kg of body weight fully protected cynomolgus monkeys challenged with aerosolized anthrax spores. Importantly, MAb 1303 defines a novel neutralizing epitope that requires Fc receptor engagement for maximal activity. F(ab')2 fragments of MAb 1303, which retain equivalent affinity for PA, are 10- to 100-fold less potent in neutralizing anthrax toxin in vitro. Addition of Fc receptor-blocking antibodies also greatly reduced the activity of MAb 1303. Moreover, we found that the neutralizing activity of mouse, rabbit, and human antisera elicited by PA vaccines was effectively abrogated by blocking Fc receptors. Selection of an anti-PA MAb by using a functional assay that is a surrogate for protection has resulted in the identification of a fully human MAb with potent activity in vivo and uncovered a previously unrecognized mechanism of antibody-mediated toxin neutralization that is important for currently used anthrax vaccines.

Bacillus anthracis edema toxin acts as an adjuvant for mucosal immune responses to nasally administered vaccine antigens.

Abstract: Anthrax edema toxin (EdTx) is an AB-type toxin that binds to anthrax toxin receptors on target cells via the binding subunit, protective Ag (PA). Edema factor, the enzymatic A subunit of EdTx, is an adenylate cyclase. We found that nasal delivery of EdTx enhanced systemic immunity to nasally coadministered OVA and resulted in high OVA-specific plasma IgA and IgG (mainly IgG1 and IgG2b). The edema factor also enhanced immunity to the binding PA subunit itself and promoted high levels of plasma IgG and IgA responses as well as neutralizing PA Abs. Mice given OVA and EdTx also exhibited both PA- and OVA-specific IgA and IgG Ab responses in saliva as well as IgA Ab responses in vaginal washes. EdTx as adjuvant triggered OVA- and PA-specific + T cells which secreted IFN-gamma and selected Th2-type cytokines. The EdTx up-regulated costimulatory molecule expression by APCs but was less effective than cholera toxin for inducing IL-6 responses either by APCs in vitro or in nasal washes in vivo. Finally, nasally administered EdTx did not target CNS tissues and did not induce IL-1 mRNA responses in the nasopharyngeal-associated lymphoepithelial tissue or in the olfactory bulb epithelium. Thus, EdTx derivatives could represent an alternative to the ganglioside-binding enterotoxin adjuvants and provide new tools for inducing protective immunity to PA-based anthrax vaccines.

Short-course postexposure antibiotic prophylaxis combined with vaccination protects against experimental inhalational anthrax

Abstract: Prevention of inhalational anthrax after Bacillus anthracis spore exposure requires a prolonged course of antibiotic prophylaxis. In response to the 2001 anthrax attack in the United States, ≈10,000 people were offered 60 days of antibiotic prophylaxis to prevent inhalational anthrax, but adherence to this regimen was poor. We sought to determine whether a short course of antibiotic prophylaxis after exposure could protect non-human primates from a high-dose spore challenge if vaccination was combined with antibiotics. Two groups of 10 rhesus macaques were exposed to ≈1,600 LD50 of spores by aerosol. Both groups were given ciprofloxacin by orogastric tube twice daily for 14 days, beginning 1–2 h after exposure. One group also received three doses of the licensed human anthrax vaccine (anthrax vaccine adsorbed) after exposure. In the ciprofloxacin-only group, four of nine monkeys (44%) survived the challenge. In contrast, all 10 monkeys that received 14 days of antibiotic plus anthrax vaccine adsorbed survived (P = 0.011). Thus postexposure vaccination enhanced the protection afforded by 14 days of antibiotic prophylaxis alone and completely protected animals against inhalational anthrax. These data provide evidence that postexposure vaccination can shorten the duration of antibiotic prophylaxis required to protect against inhalational anthrax and may impact public health management of a bioterrorism event.

Correlation between Lethal Toxin-Neutralizing Antibody Titers and Protection from Intranasal Challenge with Bacillus anthracis Ames Strain Spores in Mice after Transcutaneous Immunization with Recombinant Anthrax Protective Antigen

Abstract: Transcutaneous immunization of mice with recombinant protective antigen (rPA) of Bacillus anthracis resulted in significantly higher lethal toxin-neutralizing antibody titers than did intramuscular injection of alum-adsorbed rPA. Immunized mice were partially protected against intranasal challenge with 235,000 (10 50% lethal doses) Ames strain B. anthracis spores. A highly significant correlation was observed between toxin-neutralizing antibody titer and survival after challenge. Future experiments with rabbits and nonhuman primates should confirm the significance of protection by this vaccine strategy.

Nasal immunization with anthrax protective antigen protein adjuvanted with polyriboinosinic-polyribocytidylic acid induced strong mucosal and systemic immunities.

Abstract: The current anthrax vaccine adsorbed (AVA) was originally licensed for the prevention of cutaneous anthrax infection. It has many drawbacks, including the requirement for multiple injections and subsequent annual boosters. Thus, an easily administrable and efficacious anthrax vaccine is needed to prevent the most lethal form of anthrax infection, inhalation anthrax. We propose to develop a nasal anthrax vaccine using anthrax protective antigen (PA) protein as the antigen and synthetic double-stranded RNA in the form of polyriboinosinic–polyribocytidylic acid (pI:C) as an adjuvant. Mice were nasally immunized with recombinant PA admixed with pI:C. The resulting PA-specific antibody responses and the lethal toxin neutralization activity were measured. Moreover, the effect of pI:C on dendritic cells (DCs) was evaluated both in vivo and in vitro. Mice nasally immunized with rPA adjuvanted with pI:C developed strong systemic and mucosal anti-PA responses with lethal toxin neutralization activity. These immune responses compared favorably to that induced by nasal immunization with rPA adjuvanted with cholera toxin. Poly(I:C) enhanced the proportion of DCs in local draining lymph nodes and stimulated DC maturation. This pI:C-adjuvanted rPA vaccine has the potential to be developed into an efficacious nasal anthrax vaccine.

CpG oligonucleotides improve the protective immune response induced by the licensed anthrax vaccine.

Abstract: Synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs act as immune adjuvants, improving the response elicited by a coadministered vaccine. Combining CpG ODN with anthrax vaccine adsorbed (AVA, the licensed human vaccine) increases the speed, magnitude, and avidity of the resultant antibody response. IgG Abs against anthrax protective antigen (PA) protect mice, guinuea pigs, and rhesus macaques from infection.

Anthrax vaccines: Pasteur to the present.

Abstract: Anthrax has been a major cause of death in grazing animals and an occasional cause of death in hu- mans for thousands of years. Since the late 1800s there has been an exceptional international history of anthrax vaccine development. Due to animal vaccinations, the rate of infection has dropped dramatically. Anthrax vac- cines have progressed from uncharacterized whole-cell vaccines in 1881, to pXO2-negative spores in the 1930s, to culture filtrates absorbed to aluminum hydroxide in 1970, and likely to recombinant protective antigen in the near future. Each of these refinements has increased safety without significant loss of efficacy. The threat of genetically engineered, antibiotic and vaccine resistant strains of Bacillus anthracis is fueling hypothesis-driven research and global techniques - including genomics, proteomics and transposon site hybridization - to facili- tate the discovery of novel vaccine targets. This review highlights historical achievements and new developments in anthrax vaccine research.

Strong mucosal and systemic immunities induced by nasal immunization with anthrax protective antigen protein incorporated in liposome-protamine-DNA particles.

Abstract: The very lengthy and complicated dosing schedule of the current anthrax vaccine adsorbed, which was licensed in the USA for the prevention of cutaneous anthrax infection, calls for the development of an efficacious and easily administrable vaccine to prevent against the most lethal form of anthrax infection, the inhalation anthrax. We propose to develop a nasal anthrax vaccine using anthrax protective antigen (PA) protein carried by liposome–protamine–DNA (LPD) particles. PA was incorporated in LPD particles and nasally dosed to mice. The resulting PA-specific immune response and lethal toxin neutralization activity were measured. Mice nasally immunized with PA incorporated into LPD particles developed both systemic and mucosal anti-PA responses. The anti-PA immunities induced included the production of anti-PA antibodies (IgG and IgM in the serum and IgA in nasal and lung mucosal secretions) and the proliferation of splenocytes after in vitro stimulation. The anti-PA IgG subtype induced was mainly IgG1. Finally, anthrax lethal toxin neutralization activity was detected both in the serum and in the mucosal secretions. The anti-PA immune response induced by nasal PA incorporated in LPD was comparable to that induced by nasal PA adjuvanted with cholera toxin or subcutaneously injected PA adjuvanted with aluminum hydroxide.

Anthrax vaccination and risk of optic neuritis in the United States military, 1998-2003.

Abstract: Background Numerous case reports have suggested a possible association between optic neuritis and receipt of several different vaccines. The most frequently identified vaccines associated with optic neuritis in the literature are influenza and hepatitis B, and a report describing 2 US military cases suggests an association with the currently used anthrax vaccine (anthrax vaccine adsorbed). Objective To test the hypothesis that optic neuritis may be associated with anthrax, smallpox, hepatitis B, and influenza vaccines. Design We conducted a matched case-control study among US military personnel from January 1, 1998, through December 31, 2003, using the Defense Medical Surveillance System. Statistical associations between vaccine exposures and optic neuritis within 6-, 12-, and 18-week study intervals were estimated through multivariable conditional logistic regression analyses. Subjects A total of 1131 cases of optic neuritis and 3393 controls were matched by sex, military component, and deployment status. Results No statistically significant associations between optic neuritis and anthrax vaccine were observed for any of the 3 study intervals: 6-week interval (odds ratio [OR], 1.18; 95% confidence interval [CI], 0.74-1.87), 12-week interval (OR, 0.92; 95% CI, 0.63-0.35), and 18-week interval (OR, 0.81; 95% CI, 0.58-1.14). Furthermore, no difference in optic neuritis risk was detected when comparing those who received no dose, 1 dose, and 2 doses of anthrax vaccine. Similarly, no statistically significant associations were observed between optic neuritis and smallpox, hepatitis B, or influenza vaccines within any of the study intervals. No vaccine to vaccine interactions were statistically significant. Conclusions The results from this vaccine postmarketing surveillance investigation suggest that there is no association between optic neuritis and receipt of anthrax, smallpox, hepatitis B, or influenza vaccinations in the US military, whether these vaccines are administered alone or in combination. The negative findings presented here are important to the continuing discussions regarding the safety of these vaccines.

CpG oligonucleotides accelerate and boost the immune response elicited by AVA, the licensed anthrax vaccine.

Abstract: Synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs act as immune adjuvants, improving the immune response elicited by coadministered vaccines. Combining CpG ODN with anthrax vaccine adsorbed (AVA), the licensed human vaccine, can increase the speed, magnitude and avidity of the resultant anti-anthrax response in mice, rhesus macaques and humans. Adsorbing the CpG ODN onto cationic poly(actide-coglycolides) microparticles further boosts immunity to coadministered AVA. The antibody response induced by CpG ODN plus AVA confers protection against systemic anthrax challenge in multiple animal models. These findings suggest that CpG ODN, alone or in combination with other adjuvants and delivery strategies, may support the development of prophylactic and therapeutic vaccines against biothreat pathogens.

Recombinant protective antigen 102 (rPA102): profile of a second-generation anthrax vaccine.

Abstract: Recent terrorist attacks involving the use of Bacillus anthracis spores have stimulated interest in the development of new vaccines for anthrax prevention. Studies of the pathogenesis of anthrax and of the immune responses following infection and immunization underscore the pivotal role that antibodies to the protective antigen play in protection. The most promising vaccine candidates contain purified recombinant protective antigen. Clinical trials of one of these, recombinant protective antigen (rPA)102, are underway. Initial results suggest that rPA102 is well tollerated and immunogenic. Additional trials are necessary to identify optimal formulations and immunization regimens for pre- and postexposure prophylaxis. Future licensure of these and other candidate vaccines will depend on their safety and immunogenicity profiles in humans, and their ability to confer protection in animal models of inhalational anthrax.

Neutralizing antibodies and persistence of immunity following anthrax vaccination.

Abstract: Anthrax toxin consists of protective antigen (PA) and two toxic components, lethal factor (LF) and edema factor (EF). PA binds to mammalian cellular receptors and delivers the toxic components to the cytoplasm. PA is the primary antigenic component of the current anthrax vaccine. Immunity is due to the generation of antibodies that prevent the PA-mediated internalization of LF and EF. In this study, we characterized sera obtained from vaccinated military personnel. Anthrax vaccine is administered in a series of six injections at 0, 2, and 4 weeks and 6, 12, and 18 months, followed by annual boosters. The vaccination histories of the subjects were highly varied; many subjects had not completed the entire series, and several had not received annual boosters. We developed a simple colorimetric assay using alamarBlue dye to assess the antibody-mediated neutralization of LF-mediated toxicity to the J774A.1 murine macrophage cell line. Recently vaccinated individuals had high antibody levels and neutralizing activity. One individual who had not been boosted for 5 years had low immunoglobulin G antibody levels but a detectable neutralization activity, suggesting that this individual produced low levels of very active antibodies.

Diversity of Bacillus anthracis Strains in Georgia and of Vaccine Strains from the Former Soviet Union

Abstract: Despite the increased number of anthrax outbreaks in Georgia and the other Caucasian republics of the former Soviet Union, no data are available on the diversity of the Bacillus anthracis strains involved. There is also little data available on strains from the former Soviet Union, including the strains previously used for vaccine preparation. In this study we used eight-locus variable-number tandem repeat analyses to genotype 18 strains isolated from infected animals and humans at different sites across Georgia, where anthrax outbreaks have occurred in the last 10 years, and 5 strains widely used for preparation of human and veterinary vaccines in the former Soviet Union. Three different genotypes affiliated with the A3.a cluster were detected for the Georgian isolates. Two genotypes were previously shown to include Turkish isolates, indicating that there is a regional strain pattern in the South Caucasian-Turkish region. Four of the vaccine strains were polymorphic, exhibiting three different patterns of the cluster A1.a genotype and the cluster A3.b genotype. The genotype of vaccine strain 71/12, which is considered an attenuated strain in spite of the presence of both of the virulence pXO plasmids, appeared to be a novel genotype in the A1.a cluster.

Chloroplast-derived anthrax and other vaccine antigens: their immunogenic and immunoprotective properties

Abstract: Transgenic plants offer many advantages, including low cost of production (by elimination of fermenters), storage and transportation, heat stability, absence of human pathogens, protection of antigens in the stomach through bioencapsulation (when delivered orally), elimination of the need for expensive purification and sterile injections and generation of both systemic and mucosal immunity. Recent studies have demonstrated that chloroplast-derived anthrax-protective antigen elicits effective immune responses, develops neutralizing antibodies, confers complete protection against anthrax lethal toxin challenge and produces 360 million doses of vaccine in one acre of transgenic plants. Chloroplast-derived vaccine antigens are efficacious against bacterial, fungal, viral and protozoan pathogens.

CHAPTER 18 – Bacillus anthracis toxins

Abstract: This chapter reviews the anthrax toxins. Anthrax was recognized for many centuries as a serious disease of animals and man, one that inflicted great losses in agricultural economies and caused significant disease in humans. In domestic livestock and wild animals, symptoms of infection by Bacillus anthracis are rarely evident until the animal becomes lethargic several hours before death. The virulence of B. anthracis for animals and man depends on the production of two recognized virulence factors, the gamma-linked poly-D-glutamic acid capsule, and the three-component protein exotoxin. Virulent strains of B. anthracis contain two large plasmids, pXOl and pX02. The genes coding for toxin are contained on pXO1, and the genes for capsule are on pX02. Virulence requires the presence of both plasmids. Thus, strains lacking plasmid pXO1 do not produce toxin and are essentially avirulent in most animals, but do retain some virulence for mice. A unique feature of the anthrax toxins is the segregation of the receptor binding and translocation functions on a protein separate from the effector function. This binary design is clearly an effective one, because it is utilized by at least five other toxins produced by Gram-positive pathogens. The recognition of the need for improved anthrax vaccines has led to a great deal of study on ways to induce antibodies to PA, and to a lesser extent, LP and other potential immunogens. In fact, the great diversity of vaccine carriers being used to deliver PA will allow a useful comparison of their relative efficacies that will have a wide impact on design of other vaccines.

Recombinant viral-like particles of parvovirus B19 as antigen carriers of anthrax protective antigen.

Abstract: Viral-like particles (VLPs) of parvovirus B19 were employed as an antigen carrier to present antigenic determinants of Bacillus anthracis. The small-loop peptide and the full-length domain 4 of protective antigen (PA) were chosen as immunogens for presentation on the VLP-capsid surface and subsequent immunization of BALB/c mice. The recombinant VLPs induced anti-PA IgG titers of up to 2.5 x 10(4). Neutralization assays showed that the recombinant VLPs elicited neutralizing anti-PA antibody titers of up to 1:400 and showed potential for the prevention of lethal toxin-induced mortality of mouse-macrophage cells (RAW264.7). In postimmune sera, no anti-PA titers were detected against synthetic small-loop peptide. Recombinant VLPs demonstrated the capacity to retain the immunogenicity of the displayed microbial PA-epitopes and elicited robust levels of anti-PA antibody titers. These findings suggest that the recombinant VLPs of parvovirus B19 have potential as an additional tool in the development of sub-unit vaccines.

New-onset rheumatoid arthritis after anthrax vaccination

Abstract: Background Anthrax vaccine was licensed in 1970 and is used to protect individuals exposed to biological warfare and those who may come in contact with Bacillus anthracis in infected animals or in laboratory settings. The current adsorbed anthrax vaccine is regarded as effective and safe. Adverse effects reported include fever, chills, myalgia, arthralgia, and nausea. Four cases of rheumatoid arthritis (RA) temporally related to anthrax vaccine have been reported. As the number of administered doses increases, a better understanding of its adverse events profile will be forthcoming. Objective To describe another patient with RA temporally related to anthrax vaccination. Methods A 42-year-old man developed bilateral knee stiffness and pain in all the proximal interphalangeal joints 5 days after receiving the first dose of anthrax vaccine. He reported chills, fever, and joint and neck pain, with a tender nodule at the injection site after dose 2. Hours after receiving dose 3 he experienced fever, chills, nausea, vomiting, and neck, hand, and shoulder pain. The vaccination series was terminated after the third dose. Results Physical examination revealed moderate swelling and tenderness of his bilateral proximal interphalangeal joints. His complete blood cell count was normal; rheumatoid factor level, 198 IU/mL; erythrocyte sedimentation rate, 53 mm/h; antinuclear antibodies, negative; C-reactive protein level, 2.7 mg/L; and anti-cyclic citrullinated peptide antibody level, 168 EU. Radiographs revealed mild degenerative changes in his hands and knees bilaterally. Conclusions This case represents a fifth patient with RA temporally related to anthrax vaccine.

Treatment and Prophylaxis of Anthrax by New Neurosecretory Cytokines

Abstract: In 1881, Louis Pasteur described the Bacillus anthracis vaccine, which plays an important role for the treatment and prophylaxis of anthrax. Currently, treatment for anthrax infection involves the use of several different antibiotics, used in combination with vaccines, which possess potential virulence in white mice and guinea pigs. We discovered several new immunomodulators cytokines (polypeptides) produced by the neurosecretory cells of hypothalamus, some of which can be used as drugs for the treatment and prophylaxis of the anthrax. The proline-rich polypeptides, which consist from 10 to 15 amino acids and four proline residues, are of the special interest; one of them (PRP-1), which consist of 15 amino acids and has the following primary structure ALa-GLy-ALa-Pro-GLu-Pro-Ala-GLu-Pro-Ala-GLn-Pro-GLy-Val-Tyr (AGAPEPAEPAQPGVY) possesses antibacterial activity, and a new proline-rich peptide described by Galoyan and called G x -NH2. Both were tested for treatment against the anthrax bacillus or anthrax strain N55 vaccine in guinea pigs and mice in vivo, and in vitro preparations. The results of experiments show that these hypothalamic neurosecretory cytokines have a strong prophylaxis and therapeutic properties towards animals infected by episodic strain of anthrax and anthrax vaccine N55. The conventional concepts concerning the function of hypothalamic neurosecretion and hypothalamic mechanisms of adaptation have to be reconsidered.